Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 12, Issue 1, 2014

Atrial fibrillation is the most frequent arrhythmia in clinical practice, reaching 2% of the people in the world and is associated with systemic embolism. Thus, the use of anticoagulants is indicated if CHA2DS2-VASc score ≥2 or in patients with previous transient ischemic attack or stroke. For decades, warfarin, a vitamin K antagonist, was the only choice for chronic oral anticoagulation. Recently, novel oral anticoagulants (NOACs) have been introduced, offering similar (or better) effectiveness, safety, and convenience to the vitamin K antagonists. Dabigatran was the first NOAC approved and is a direct thrombin inhibitor. Rivaroxaban and apixaban are factor Xa inhibitors. They display rapid onset of action, more predictable of pharmacological profile, less interactions with other drugs, lack of significant effects in the diet, and less risk of intracranial hemorrhage than warfarin. Despite that dose adjustment is necessary for patients with chronic kidney disease or according to body weight, these new drugs do not require regular monitoring. There are recommendations for the start and follow-up therapy with NOACs, planning for cardioversion, ablation and surgical interventions and the management of bleeding. This article is a review of the major studies of the NOACs. The clinical use of these drugs in patients with non-valvular atrial fibrillation is presented.

Novel oral anticoagulants (NOACs) have been developed as alternatives for vitamin K antagonists (VKAs) for the prevention of thromboembolic events in patients with a variety of medical conditions. In this review, we summarize the current data on NOACs safety and efficacy compared to VKAs and in specific patients’ groups including heart valve replacement, venous thromboembolism, advanced renal failure and the elderly.

The patients experiencing an acute coronary event are exposed to increased risk of thromboembolic events. That risk becomes substantially greater when AF fibrillation and heart failure are present as well. Dual antiplatelet therapy remains the gold standard in the treatment of patients with ACS. The combination of an oral anticoagulant agent with dual antiplatelet therapy is proven to be more effective in prevention of further antithrombotic events but is followed by increased risks of clinically significant bleeding thus it is not suggested in the treatment of ACS. However, it has been proven beneficial in patients with AF who present with an acute coronary episode. NOACs have proved to be at least as effective as vitamin K antagonists in protecting patients with atrial fibrillation from thromboembolic events without increased risk of major bleeding. However, only data on the effectiveness of NOACS in patients with ACS and AF have been quite contradictory. Even more, the data on the effect of NOACS in patients with concomitant HF and AF who present with an acute coronary event is almost lacking from current bibliography. In this review, we attempt to describe the available data of the use of NOACS in patients with AF and HF who experience an ACS and to address the need for further studies in this area.

Atherosclerosis comprises of a chronic disease of the vessels which mainly targets the arterial system. The disease’s main characteristic is the accumulation of inflammatory cells, lipids, smooth muscle cells and connective tissue within the vascular intima layer. The atherosclerotic lesion can be more accurately defined as a fibro-inflammatory lipid plaque. The pathogenesis of the atherosclerotic plaque is a progressive and additive process that usually occurs over decades. Antiplatelet and anticoagulant agents have been the major elements of large trials since decades, in an attempt to promote the primary and secondary prevention of atherothrombosis. The atherosclerotic plaque rupture and the following thrombosis involve, among others, activation of both platelets and coagulation factors, therefore a potential combination of antiplatelet and anticoagulant therapy, particularly in the setting of secondary prevention has been reconsidered in the light of the newly developed oral anticoagulants.

Polycythemia vera and essential thrombocythemia comprise myeloproliferative neoplasms, the main characteristic of which is an over-production of bone marrow myeloid lineage cells. The diseases typically involve thrombosis and their treatment, apart from the strictly hematological aspect, involves antithrombotic agents. In this review we aspire to present the possible role of the newly developed oral anticoagulants in the treatment scheme of polycythemia vera and essential thrombocythemia.

G protein-coupled receptors (GPCRs) constitute several membrane proteins that are turned on by hormones and neurotransmitters to trigger cellular signaling pathways. GPCRs have been targeted in the development of several drugs but the therapeutic potential of these proteins remains underutilized. Most drugs to date have targeted the class A, or the rhodopsin family of GPCRs, but recently the Class B, i.e., the secretin family of G protein receptors has been targeted for the treatment of metabolic diseases such as diabetes mellitus. Class B G protein-coupled receptors (GPCRs) have also been targeted for managing several clinical conditions such as diabetes mellitus, bone disorders, malignancies, neurodegeneration, cardiovascular diseases, neuropsychiatric disorders, etc. In this article, we review the medicinal chemistry and potential clinical role of targeting GPCRs with a special emphasis on cardiovascular pharmacology.

Atrial fibrillation affects approximately 5 million patients in the United States. The rate of stroke in adults with atrial fibrillation depending on their risk factors varies between 1-20% annually. Anticoagulation with vitamin K antagonists such as warfarin has been the mainstay therapy but it is cumbersome and requires close follow-up. Since 2010, three new oral anticoagulants have received Food and Drug Administration approval for stroke prevention in atrial fibrillation. This review summarizes data from three landmark trials: RE-LY, ROCKET-AF, and ARISTOTLE. In addition, issues relating to cost, reversal, drug interactions, and perioperative discontinuation are discussed. Compared to Warfarin, Dabigatran 150mg twice daily lowered the primary outcome of stroke/systemic embolism by 34% (number needed to treat/yr 169) and had similar incidence of major bleeding. Rivaroxaban demonstrated non inferiority compared to the warfarin group for the primary outcome of stroke and systemic embolism and major bleeding. Apixaban showed a relative risk reduction for the primary outcome of 21% (number needed to treat 300), and lowered major bleeding down by 31% (number needed to treat /yr 104). Apixaban also showed a mortality benefit compared to warfarin (3.52 vs. 3.94%/year, p 0.047). All 3 oral anticoagulants lowered rates of intracranial hemorrhage. The use of Rivaroxaban and Apixaban has been projected to reduce medical costs when compared to warfarin, and Dabigatran is projected to have similar costs. All the 3 oral anticoagulants have robust randomized controlled trials supporting their comparability to warfarin therapy for stroke prevention in non valvular atrial fibrillation, with Apixaban showing superiority in incidence of strokes, major bleeding and mortality.

Heparin-induced thrombocytopenia (HIT) is a life and limb-threatening thrombotic complication of heparin, which is the result of platelet activation by anti-PF4/heparin antibodies. With lepirudin and danaparoid no longer available in the US, treatment options are limited to argatroban, fondaparinux (off-label use) and bivalirudin (for patients undergoing percutaneous coronary intervention). Both argatroban and bivalirudin are parenteral drugs and require close monitoring and hospitalization. Fondaparinux is contraindicated in patients with significant renal impairment and is associated with a small risk of HIT. Anticoagulants approved for thromboprophylaxis and management of thromboembolic conditions such as rivaroxaban, dabigatran, and apixaban have fixed oral dose, rapid onset of action and does not require monitoring. These novel agents do not interact with anti-PF4/heparin antibody and offer attractive therapy options for HIT. Their utility in HIT has been supported by a few clinical reports, however, larger studies are needed before they can be utilized in clinical practice. Therapeutic plasma exchange has been utilized with some success in patients with HIT, who need heparin reexposure for cardiac surgery but their safety and efficacy needs further exploration. 2-O, 3-O desulfated heparin, which lacks any anticoagulant effect, has been shown to reduce the development of HIT in murine models. Finally, novel targets based on the molecular pathogenesis of HIT are being studied for therapeutic drug development. We hope that the availability of novel therapies in the future will expand the options available for the management of HIT.